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Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate.

In uremia there is a marked elevation of serum levels of indoxyl sulfate due to its decreased renal clearance. Indoxyl sulfate is synthesized in the liver from indole which is produced by bacteria in the intestines. To determine the role of indoxyl sulfate in the progression of chronic renal failure, we administered indole, the precursor of indoxyl sulfate, to subtotally nephrectomized uremic rats. The oral administration of indole increased the serum levels of creatinine and blood urea nitrogen and decreased creatinine, inulin, and p-aminohippuric acid clearances. The glomerular sclerosis index in the indole-treated rats was higher than in the control uremic rats. After oral administration, indole could not be detected in the urine, but large amounts of its metabolite, indoxyl sulfate. Thus, indole administration stimulated glomerular sclerosis in a uremic model through the production of indoxyl sulfate.

Animals↗

Uremic intoxication.

The toxic effects of metabolites that are known to accumulate in renal failure are described and the role that they may play in causing uremic symptoms is considered. The opinion of the Authors is that all they are likely to take a lesser or greater part in uremic intoxication. Methylguanidine seems to be very important in this context while for some others (like amines) nothing can be stated for studies on their chronic toxicity are lacking. The hypothesis is also considered of the accumulation of unidentified toxic metabolites with a middle molecular weight. It is stated, as to this problem, that the clinical evidence apparently supporting univocally their existence, is instead also consistent with the hypothesis of toxins (like methylguanidine) having a preferential distribution in the intracellular fluid compartment.

Amines↗

Profiling of endogenous ligand solutes that bind to serum proteins in sera of patients with uremia.

The profiling of endogenous ligand solutes in sera of patients with uremia was performed by using an ultrafiltration device and high-performance liquid chromatography. Seventeen endogenous ligand solutes, which are ultraviolet-absorbing substances, were detected in a sample volume of 40 microliters, and four ligand solutes were tentatively identified as indoxylsulfate, hippuric acid, 2-hydroxybenzoylglycine, and 3-indoleacetic acid. One of these ligand solutes designated as peak P was thought to be a candidate for a major drug-binding inhibitor in uremia.

Blood Proteins↗

Inhibition of hepatic glutathione S-transferases by a major endogenous ligand substance present in uremic serum.

A major endogenous ligand substance present in uremic serum, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, inhibited the in vitro activity of bovine and rat liver glutathione S-transferases. Our results suggested that endogenous ligand substances retained in uremic serum have some toxic activities other than the inhibition of drug binding to serum protein observed in uremia.

Animals↗

Effect of hemodialysis on serum concentrations of HPLC-analyzed accumulating solutes in uremia.

The concentration changes, during hemodialysis treatment, of 18 characteristic uremia compounds, analyzed by high-pressure liquid chromatography in sera of renal patients were studied. Pre- to postdialysis concentration ratios (dialysis ratio, D) varied from 0.83 to 3.04 for the different solutes. A division into three solute groups, on the basis of their D values, could be rationalized qualitatively from data on protein binding and dialyzer clearance. One group showed low dialysis ratios which could be explained from plasma protein binding. The second group had intermediate D values, comparable to those of creatinine. For some of the members of the third group, high D values might indicate a compartmentalization and resistance to mass transfer across biological membranes. Among the latter are the tubularly secreted hippuric acid and p-hydroxyhippuric acid. For most of the (protein-bound) solutes, protein binding was shown to decrease during hemodialysis. Protein binding levels were higher after dialysis only for hippuric acid and the as yet unidentified fluorescent solute designated UFK8. In conclusion, the change of serum concentrations and of protein binding resulting from hemodialysis treatment are presented and are compared for 18 accumulating solutes in sera of patients with end-stage renal failure.

Adult↗

Inhibitory effect of oral sorbent on accumulation of albumin-bound indoxyl sulfate in serum of experimental uremic rats.

Serum indoxyl sulfate, which is markedly accumulated in uremic patients, cannot be removed efficiently by hemodialysis due to its albumin binding. To determine if oral adsorbent (AST-120) can decrease its serum concentration in uremic state, oral adsorbent was administered to experimental nephrectomized uremic rats. Uremic rats fed with oral adsorbent showed a significantly lower serum concentration of indoxyl sulfate compared to control uremic rats, even when serum concentrations of urea nitrogen and creatinine were not significantly decreased in the uremic rats fed with oral adsorbent. Indoxyl sulfate was detected only at a lower concentration in bile as compared with the serum of uremic rats. These results suggest that oral adsorbent adsorbs indole, a precursor of indoxyl sulfate, in the intestine and prevents the accumulation of indoxyl sulfate in uremic rats.

Administration, Oral↗

Purple urine bag syndrome.

Purple pigment extracted from the urinary catheters and collecting bags of two elderly female patients was analysed by a variety of chemical techniques, including mass spectroscopy and nuclear magnetic resonance. Although previous studies identified the pigment as indigo, we failed to confirm this. Our analysis also demonstrated that indicanuria is not a requirement for the production of the pigment and furthermore indicates that the molecular structure of the pigment is either a steroidal or bile acid conjugate.

Aged↗

Case report: purple urine bag syndrome.

Purple urine bag syndrome (PUBS) was first reported in 1978. PUBS is rare, occurs predominantly in constipated women, chronically catheterized and associated with some bacterial urinary infections that produce sulphatase/phosphatase. The etiology is due to indigo (blue) and indirubin (red) or to their mixture that becomes purple. A chain reaction begins in the gastrointestinal tract with tryptophan as described in the article.

Catheters, Indwelling↗

A furan fatty acid and indoxyl sulfate are the putative inhibitors of thyroxine hepatocyte transport in uremia.

We studied the effects of 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), indoxyl sulfate, and hippuric acid on iodide production by rat hepatocytes in primary cultures. We questioned whether these substances could explain the alteration of serum thyroid hormone parameters observed in renal failure. Iodide production from [125I]T4 by rat hepatocytes was significantly inhibited in the presence of serum from uremic patients. Serum concentrations of CMPF, indoxyl sulfate, and hippuric acid were markedly elevated in uremic patients. The minimum concentration that inhibited iodide production, when expressed as a molar ratio of the inhibitor to BSA, was 0.13 for CMPF, 0.53 for indoxyl sulfate, and 1.33 for hippuric acid. This molar ratio was lower than the corresponding mean molar ratio in uremic sera for CMPF (0.38) and indoxyl sulfate (0.63), while it was higher than that found for hippuric acid (0.85). The inhibition was reproduced when the inhibitors were added to normal human serum. The decreased iodide production was not due to the inhibition of deiodinase activity. The deiodination of rT3 by rat liver microsomes was unaffected by these inhibitors. Charcoal adsorption of uremic serum normalized the iodide production by hepatocytes. This normalization coincided with almost complete removal of CMPF and indoxyl sulfate, with a concomitant reduction of the free T4 fraction. Dialysis of uremic serum only partially restored iodide production. Even though indoxyl sulfate and hippuric acid were no longer detectable, a high concentration of CMPF remained in the serum. The serum free T4 fraction remained elevated in uremic patients after dialysis. Our studies indicate that CMPF and indoxyl sulfate in concentrations normally present in the serum of uremic patients inhibit cellular transport and subsequent deiodination of T4. These substances may account for the low total T3 level in uremic patients.

Adsorption↗

In-vitro study on the competitive binding of diflunisal and uraemic toxins to serum albumin and human plasma using a potentiometric ion-probe technique.

The competitive binding of diflunisal and three well-known uraemic toxins (3-indoxyl sulfate, indole-3-acetic acid and hippuric acid) to bovine serum albumin (BSA), human serum albumin (HSA) and human plasma was studied by direct potentiometry. The method used the potentiometric drug ion-probe technique with a home-made ion sensor (electrode) selective to the drug anion. The site-oriented Scatchard model was used to describe the binding of diflunisal to BSA, HSA and human plasma, while the general competitive binding model was used to calculate the binding parameters of the three uraemic toxins to BSA. Diflunisal binding parameters, number of binding sites, n(i) and association constants for each class of binding site, K(i), were calculated in the absence and presence of uraemic toxins. Although diflunisal exhibits high binding affinity for site I of HSA and the three uraemic toxins bind primarily to site II, strong interaction was observed between the drug and the three toxins, which were found to affect the binding of diflunisal on its primary class of binding sites on both BSA and HSA molecules and on human plasma. These results are strong evidence that the decreased binding of diflunisal that occurs in uraemic plasma may not be solely attributed to the lower albumin concentration observed in many patients with renal failure. The uraemic toxins that accumulate in uraemic plasma may displace the drug from its specific binding sites on plasma proteins, resulting in increased free drug plasma concentration in uraemic patients.

Algorithms↗

Precocious puberty in a patient with indicanuria.

A 7-5/12 year-old girl, who was followed-up after diagnosis of indicanuria, presented with symptoms of bilateral breast enlargement. Her breast development was at Tanner stage II. No pubic or axillary hair was observed. Pelvic ultrasonography revealed multiple follicles on both ovaries. Basic endocrinological evaluation and cranial magnetic resonance imaging (MRI) were normal. The diagnosis of precocious puberty was established with respect to the pubertal response to GnRH stimulation test. Although precocious puberty has been reported associated with some metabolic diseases, this is the first description in a patient with indicanuria. The question of whether precocious puberty in our patient with indicanuria is a coincidence or whether it is related to metabolic changes activating the hypothalamo-pituitary-gonadal axis remains open.

Amino Acid Metabolism, Inborn Errors↗

Purple urine bag syndrome in a hemodialysis patient.

Purple urine bag syndrome (PUBS) is an uncommon disorder, in which the plastic disposable urinary catheter bag turns purple or blue following hours or days of urinary catheterization. The purple discoloration results from indirubin dissolved in the plastic mixing with indigo in the urine. Bacteria possessing indoxyl sulfatase degrade indoxyl sulfate into indirubin and indigo. Indoxyl sulfate is derived from the metabolism of tryptophan. PUBS usually occurs in chronic catheterized elderly women who are constipated and poorly ambulant. The clinical course is benign and rarely causes sepsis. This investigation reports a 61-year-old female diabetic patient with end-stage renal disease on maintenance hemodialysis, who had two episodes of blue or purple urine bag discoloration. The urine culture of the first episode yielded Klebsiella pneumoniae, whereas that of the second episode yielded Escherichia coli, Enterococcus faecalis, and Proteus vulgaris. Both episodes resolved following oral antibiotics treatment and placement of new foley catheters. To our knowledge, this is the first recorded case of PUBS in a dialysis patient.

Bacteria↗

[Five cases of purple urine bag syndrome in a geriatric ward].

We report five cases of purple urine bag syndrome (PUBS). All the patients were women and they had been bed-ridden for a long period due to cerebrovascular diseases. They tended to be constipated as a result of habitual use of laxatives. Indicanuria was proven in the all urinary samples from the patients. The four assessable urinary cultures showed Proteus mirabilis contamination. Total days without evacuation per month in patients with PUBS and control subjects (5 catheterized subjects without PUBS) were 16.5 +/- 3.7 and 6.8 +/- 4.8, respectively (mean +/- SD), showing a significant difference (p < 0.05). In each case, this syndrome was not considered to have affected their clinical course. We concluded that it is unnecessary to treat patients with PUBS aggressively. Control of evacuation and urological sanitation are important in these patients.

Aged↗

Association between blood indoxyl sulfate and carbonyl stress marker in hemodialysis patients.

BACKGROUND: Indoxyl sulfate (IS) is a protein-bound solute, which is progressively retained in blood according to the decline of renal function. However, clinical relevance of excess IS in hemodialysis (HD) patients remains unknown. PATIENTS AND METHODS: We measured serum IS and clinical parameters including pentosidine, carboxymethyllysine (CML) and homocysteine levels in 55 HD patients (age: 67 +/- 2 years, time on HD: 67 +/- 11 months, male/female = 30/25), and examined the relationship between IS and these data. RESULTS: Serum IS was markedly increased in HD patients (80.49 +/- 6.17 microg/ml) compared to normal range (< 1.9 microg/ml). IS was significantly and positively correlated with time on HD (p < 0.01), blood urea nitrogen (p < 0.01), beta2-microglobulin (p < 0.03), and protein catabolic rate (PCR) (p < 0.01). The patients with increased IS needed a higher erythropoietin dosage. Blood IS was positively correlated with pentosidine (r = 0.505, p < 0.01) and CML (r = 0.275, p < 0.05). In contrast, blood IS was not associated with nutritional and inflammatory parameters. A stepwise multiple regression analysis revealed that time on HD, PCR and pentosidine were significant determinants of IS. CONCLUSIONS: Serum IS was related to time on HD and dietary protein intake. Accumulated IS may be associated with enhanced carbonyl stress in chronic HD patients.

Adult↗